Phenylethylamines and condensed rings variants as prodrugs of catecholamines, and their use

ABSTRACT

Compounds of the general formula I 
                         
wherein rings B, C, D and E may be present or not and, when present, are combined with A as A+C, A+E, A+B+C, A+B+D, A+B+E, A+C+E, A+B+C+D or A+B+C+D+E, rings B, C and E being aliphatic whereas ring D may be aliphatic or aromatic/heteroaromatic, and wherein X is —(CH 2 ) m —, in which m is an integer 1-3, to form a ring E or, when E is absent, a group R 1  bound to the nitrogen atom, wherein R 1  is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 3 carbon atoms, cycloalkyl(alkyl) groups of 3 to 5 carbon atoms (i.e. including cyclopropyl, cyclopropylmethyl, cyclobutyl and cyclobutylmethyl) and wherein Y is —(CH 2 ) n —, in which n is an integer 1-3, to form a ring C or when C is absent, a group R 2  bound to the nitrogen atom, wherein R 2  is selected from the group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 7 carbon atoms, cycloalkyl(alkyl) groups of 3 to 7 carbon atoms, alkenyl or alkylnyl groups of 3 to 6 carbon atoms, arylalkyl, heteroarylalkyl having 1 to 3 carbon atoms in the alkyl moiety, whilst the aryl/heteroaryl nucleus may be substituted, provided that when rings B, C, D and E are absent NR 1 R 2  is different from dimethylamino, N-methyl-N-ethylamino, N-methyl-N-propynyl-amino, N-methyl-N-propylamino and N-hydroxipropyl-N-methylamino, and salts thereof with pharmaceutically acceptable acids or bases are disclosed as well as the use of such compounds for the manufacturing of pharmaceutical compositions for the treatment of Parkinson&#39;s disease, psychoses, Huntington&#39;s disease, impotence, renal failure, heart failure or hypertension, such pharmaceutical compositions and methods of treating Parkinson&#39;s disease and schizophrenia.

Notice: More than one reissue application has been filed for the reissueof U.S. Pat. No. 6,998,405. The reissue applications are applicationSer. Nos. 12/945,057 (the present application) and 11/790,465, both ofwhich are divisional reissues of U.S. Pat. No. 6,998,405.

RELATED APPLICATIONS

This application is a divisional reissue of application Ser. No.11/790,465, filed on Apr. 25, 2007, now U.S. Pat. No. RE42,802, which isa reissue of application Ser. No. 10/737,782, filed on Dec. 18, 2003,now U.S. Pat. No. 6,998,405, which is a divisional of application Ser.No. 10/258,014 filed Oct. 18, 2002 now U.S. Pat. No. 6,683,087, which isa 371 of PCT/SE01/00840, filed Apr. 17, 2001.

FIELD OF THE INVENTION

The present invention relates to new chemical compounds representing anew prodrug principle for the generation of catecholamines, inparticular catecholethylamines, to processes for their preparation,pharmaceutical compositions containing them and their use in therapy.

BACKGROUND ART

Neurodegenerative diseases are becoming more prevalent with the agingpopulation. One particular neurodegenerative disease which typically hasits onset between the ages of 50 and 80 years of age is Parkinson'sdisease. Parkinson's disease is a disorder of the brain which ischaracterized by tremor and difficulty with walking, movement, andcoordination.

Parkinson's disease appears to be caused by a progressive deteriorationof dopamine-containing neurons in the substantia nigra zona compacta ofthe brain. Dopamine is a chemical neurotransmitter which is utilized bybrain cells to transmit impulses to control or modulate peripheralmuscle movement. The loss of the dopamine-containing neurons results inreduced amounts of dopamine available to the body. Insufficient dopamineis thought to disturb the balance between dopamine and otherneurotransmitters such as acetylcholine. When such dopamine levels arereduced, nerve cells cannot properly transmit impulses, resulting in aloss of muscle control and function.

Currently, there is no known cure for Parkinson's disease. Treatmentsare typically aimed at controlling the symptoms of Parkinson's disease,primarily by replacing the dopamine, with either L-DOPA which ismetabolized to dopamine, or by administering chemical agents thatstimulate dopamine receptors. Current treatments to slow the progressionof the disease include compounds such as deprenyl (Selegeline), aselective monoamine oxidase inhibitor, and amantadine, a compound thatappears to decrease dopamine uptake into presynaptic neurons.

Certain hydroxylated (mono-phenolic or catechols) phenylethylamines (assuch or forming part of a semi-rigid/rigid ring system) are known tohave useful dopaminergic activity. However, their clinical use islimited because they have low or no bioavailability (high first-passeffect).

It has been reported that(±)-5-keto-2-N,N-di-n-propylamino-tetrahydrotetralin ((±)-5-keto-DPATT(Formula A)) does possess dopaminergic effects in rats in vivo. However,in vitro binding of this compound does not take place, i.e.(±)-5-keto-DPATT has itself no affinity to DA receptors. Consequently,it must be bioactivated before displaying its effects. This waspublished on a poster by Steven Johnson at a local Med. Chem. Meeting inAnn Arbor, Mich., USA in 1994. There was no mentioning of catecholamineformation on that poster. However, it was speculated, but not shown,that the active drug may be (±)-5-OH-DPAT (see Formula B below).Consequently, the compound of Formula II, falling within the generallyclaimed structure of Formula I, is provisoed from the present invention.

In recent years a large body of pharmacological, biochemical andelectrophysiological evidence has provided considerable support in favorof the existence of a specific population of central autoregulatorydopamine (DA receptors) located in the dopaminergic neuron itself andbelonging to the D2 receptor subclass of DA receptors. These receptorsare part of a homeostatic mechanism that modulates nerve impulse flowand transmitter synthesis and regulates the amount of DA released fromthe nerve endings. Recently, Sokoloff, et al., Nature, 347 146-51 (1990)presented evidence for the existence of a new type of dopamine receptorcalled D3. In a series of screened classical and a typical neuroleptics,the preferential dopamine autoreceptor antagonists (+)-AJ76 and(+)-UH232 possessed the highest preference for the D3 site. The D3receptor appears to occur both pre- and postsynaptically, and theregional distribution (high preference in limbic brain areas) differsfrom that of the D1 and D2 receptors.

Drugs acting as agonists or antagonists on central DA transmission areclinically effective in treating a variety of central nervous systemdisorders such as parkinsonism, schizophrenia, Huntington's disease andother cognitive dysfunctions.

In parkinsonism, for example, the nigro-neostriatal hypofunction can berestored by an increase in postsynaptic DA receptor stimulation (seeabove)). In schizophrenia, the condition can be normalized by achievinga decrease in postsynaptic DA receptor stimulation. Classicalantipsychotic agents directly block the postsynaptic DA receptor. Thesame effect can be achieved by inhibition of intraneuronal presynapticevents essential for the maintenance of adequate neurotransmission,transport mechanism and transmitter synthesis.

Direct DA receptor agonists, like apomorphine (a mixed DA D1/D2agonist), are able to activate the DA autoreceptors as well as thepostsynaptic DA receptors. The effects of autoreceptor stimulationappear to predominate when apomorphine is administered at low doses,whereas at higher doses the attenuation of DA transmission is outweighedby the enhancement of postsynaptic receptor stimulation. Theantipsychotic and antidyskinetic effects in man of low doses ofapomorphine are likely due to the autoreceptor-stimulator properties ofthis DA receptor agonist. This body of knowledge indicates DA receptorstimulants with a high selectivity for central nervous DA autoreceptorswould be valuable in treating psychiatric disorders.

Compounds displaying preferential antagonistic effects at DAautoreceptors have been developed, Johansson et al., J. Med. Chem., 28,1049 (1985). Examples of such compounds are(+)-cis-1S,2R-5-methoxy-1-methyl-2-(N-n-propylamino)tetralin((+)-1S,2R-AJ76) and(+)-cis-1S,2R-5-methoxy-1-methyl-2-(N,N-di-n-propylamino)tetralin((+)-1S,2R-UH232). Biochemically these compounds behave as classical DAantagonists, e.g. like haloperidol. Consequently, they raise the Dopaaccumulation in normal animals after the blockage of aromatic amino aciddecarboxylase by NSD1015 and they raise the levels of the DA metabolitesDOPAC and HVA (no NSD1015 treatment). However, functionally, inbehavioral testing (photocell motility meters), they display stimulatoryproperties, e.g. they increase the locomotor activity. In addition,gross behavioral observations show that these compounds, in certaindosages, can induce a weak classical dopaminergic stereotypic behavioraleffects like sniffing and rearing in rodents.

Diseases in which an increase in dopaminergic turnover may be beneficialare geriatrics, for preventing bradykinesia and depression and in theimprovement of mental functions (e.g. cognition). It can have an effectin depressed patients. It can be used in obesitas as an anorectic agent.It can improve minimal brain dysfunction (MBD), narcolepsy and negativesymptoms of schizophrenia and, in addition, impotence, erectiledysfunction and restless legs. Thus, improvement of sexual functions isanother indication (in both women and men).

DISCLOSURE OF THE INVENTION

It is an object of the present invention to provide new prodrugs whichare uniquely metabolized in vivo to a catecholamine derivative that is apotent dopamine receptor ligand with agonist, partial agonist, inverseagonist and/or antagonist effects.

According to the present invention there is now provided new compoundshaving the general structural formula (I)

wherein rings B, C, D and E may be present or not and, when present, arecombined with A as A+C, A+E, A+B+C, A+B+D, A+B+E, A+C+E, A+B+C+D orA+B+C+D+E, rings B, C and E being aliphatic whereas ring D may bealiphatic or aromatic/heteroaromatic, and wherein X is —(CH₂)_(m), inwhich m is an integer 1-3, to form a ring E or, when E is absent, agroup R₁ bound to the nitrogen atom, wherein R₁ is selected from thegroup consisting of a hydrogen atom, alkyl or haloalkyl groups of 1 to 3carbon atoms, cycloalkyl(alkyl) groups of 3 to 5 carbon atoms (i.e.including cyclopropyl, cyclopropylmethyl, cyclobutyl andcyclobutylmethyl) and wherein Y is —(CH₂)_(n)—, in which n is an integer1-3, to form a ring C or when C is absent, a group R₂ bound to thenitrogen atom, wherein R₂ is selected from the group consisting of ahydrogen atom, alkyl or haloalkyl groups of 1 to 7 carbon atoms,cycloalkyl(alkyl) groups of 3 to 7 carbon atoms, alkenyl or alkylnylgroups of 3 to 6 carbon atoms, arylalkyl, heteroarylalkyl having 1 to 3carbon atoms in the alkyl moiety, whilst the aryl/heteroaryl nucleus maybe substituted, provided that when rings B, C, D and E are absent NR₁R₂is different from dimethylamino, N-methyl-N-ethylamino,N-methyl-N-propynyl-amino, N-methyl-N-propylamino andN-hydroxipropyl-N-methylamino, and salts thereof with pharmaceuticallyacceptable acids or bases.

The compounds thus disclaimed are known per se but their therapeuticaluse has not been disclosed previously.

Thus the present invention provides the following classes of compoundsbased on the different combinations of rings A to E:

wherein R₁, R₂, m and n are defined as above.

The preferred combinations for rings A to E are A+B+C (formula Ie),A+B+C+D (formula Ig), A+B+E (formula If), A+E (formula Ib) and A+C+E(formula Id), the most preferred combination being that of A+B+C(formula Ie).

The preferred meaning of R₁ and R₂ is n-propyl.

It will be apparent to those skilled in the art that compounds of thisinvention contain one or several chiral centers. The compounds ofFormula I contain asymmetric carbon atoms in the alphatic ring moieties.The scope of this invention includes all (theoretically possible)R/S-combinations of the compounds of Formula I in their pure form. Ingeneral, the flatter a molecule of Formula I is the more potent it is asa dopaminergic agonist, provided it has a suitable n-alkyl substituent.Flat molecules of Formula I are those which have transfused ringsystems.

Since the pharmaceutical activity of the racemates or the differentcombinations of R/S at the chiral C atoms in a molecule of the presentinvention can differ, it may be desirable to use as “chirally” pureforms as possible (e.g. the examples given below). In these cases, thefinal product or else even the intermediates can be resolved intoenantiomeric compounds by chemical or physical measures known to theperson skilled in the art or even employed in the synthesis as such.

Preferred absolute configurrations of compounds of Formula Ia-h

wherein R₁, R₂, m and n are defined as above.

The prodrugs according to the present invention display usefultherepeutic effects for the treatment of diseases like (in the centralnervous systen (CNS)): Parkinson's disease, psychoses (e.g.schizophrenia), Huntington's disease, impotence; (in the periphery):renal failure, heart failure and hypertension. Other fields oftherapeutically active catecholamines are adrenergic, anti-adrenergiccompounds.

Some of the compounds according to the invention have both pre- andpostsynaptic antagonistic effects. Compounds possessing more of thepostsynaptic effects can be used to alleviate the symptoms (bothpositive and negative) of schizophrenia and for the rehabilitation ofdrug addicts. Other disturbances of interest in this context is “jetlag”, sleep disorders and early stages of Parkinsonism. Anotherindication for the compounds of this invention are diseases with adisturbed cognition, e.g. Huntington's disease and Alzheimer's disease.

Other diseases/conditions, beside Parkinson's disease, which can betreated with the compounds, in a suitable formulation, of the presentinvention are restless legs syndrome (RLS), erectile dysfunction(impotence in men) and sexual stimulation in e.g. menopausal women(stimulation of vaginal lubrication and erection of clitoris). In theautoreceptor dose-range, corresponding to a low plasma and striataltissue concentration of compounds of the present invention can also beused to treat psychoses (e.g. schizophrenia; see above).

The herewith mentioned diseases do not form a limitation to the presentinvention, thus, other diseased states involving the DA-ergic system mayalso be relevant for treatment with compounds of the present invention.

The compounds of Formula I may be converted to their respective“built-in” 3,4-di-OH-phenylethylamines, (Formula II), in vivo in the CNSand/or the periphery.

wherein X, Y, R₁, R₂, m and n are defined as above in connection withformula I.

It is possible that the compounds of Formula II appear in the braincells of animals following oral and parenteral administration of thecompounds of Formula I. Therefore, in accordance with the presentinvention, applicants have surprisingly found thatcyclohexenone-ethylamines of the general structure of Formula I aboveare bio-activated in vivo, likely to the corresponding3,4-di-OH-phenylethylamines (Formula II).

Compounds of formula II may also possess properties ofcatechol-O-methyl-transferase (COMT) inhibition, an effect which maysynergistically augment the dopaminergic effects of the catecholsgenerated.

The compounds of the present invention can be administered to a patienteither alone or as a part of a pharmaceutical composition.

The term “patient” as used herein means all animals including humans.Examples of patients include humans, rodents, and monkeys.

Thus, according to another aspect of the present invention here isprovided a pharmaceutical composition which as the active principlecontains a compound of formula I as defined above, however with nodisclaimer in the meaning of NR₁R₂ when rings B, C, D and E are absent,or a pharmaceutically acceptable salt thereof together with apharmaceutically acceptable carrier, diluent, or excipient.

The pharmaceutical compositions of the present invention can beadministered to patients either orally, rectally, parenterally(intravenously, intramuscularly, or subcutaneously), intracisternally,intravaginally, intraperitoneally, intravesically, locally (powders,ointments, or drops), or as a buccal or nasal spray.

A preferred route of administration is oral, although parenteral andtransdermal administration are also contemplated. Controlled releaseformulations particularly in the form of skin patches and the like, areparticularly well-suited treating elderly patients.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable (such as olive oil, sesame oil and viscoleo) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of a coating such as lecithin, by themaintenance of the required particle size in the case of dispersions andby the surfactants.

These compositions may also contain adjuvants such as preserving,emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms be controlled by addition of any of various antibacterialand antifungal agents, example, parabens, chlorobutanol, phenol, sorbicacid, and the like. It may also be desirable to include isotonic agents,for example sugars, sodium chloride, and the like. Prolonged absorptionof the injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

Oral delivery of the invention compounds is preferred, given the typicalage of the patient population and the condition being treated. Soliddosage forms for oral administration include capsules, tablets, pills,powders and granules. In such solid dosage forms, the active compound isadmixed with at least one inert customary excipient (or carrier) such assodium citrate or dicalcium phosphate or:

-   (a) fillers or extenders, as for example, starches, lactose,    sucrose, glucose, mannitol and silicic acid,-   (b) binders, as for example, carboxymethylcellulose, alginates,    gelatin, polyvinylpyrrolidone, sucrose, and acacia,-   (c) humectants, as for example, glycerol-   (d) disintegrating agents, as for example, agar-agar, calcium    carbonate, potato or tapioca starch, alginic acid, certain complex    silicates, and sodium carbonate,-   (e) solution retarders, as for example paraffin,-   (f) absorption accelerators, as for example, quaternary ammonium    compounds,-   (g) wetting agents, as for example cetyl alcohol, and glycerol    monostearate,-   (h) adsorbents, as for example, kaolin and bentonite, and-   (i) lubricants, as for example, talc, calcium stearate, magnesium    stearate, solid polyethylene glycols, sodium lauryl sulfate, or    mixtures thereof. In the case of capsules, tablets, and pills, the    dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar and as high molecular weight polyethylene glycols, and thelike.

Solid dosage forms such as tablets, dragées, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well known in the art. They may contain opacifyingagents, and can also be of such composition that they release the activecompound or compounds in a certain part of the intestinal tract in adelayed manner. Examples of embedding compositions which can be used arepolymeric substances and waxes. The active compounds can also be used inmicro-encapsulated form, if appropriate, with one or more of theabove-mentioned excipients. Controlled slow release formulations arealso preferred, including osmotic pumps and layered delivery systems.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethylformamide, oils, in particular, cottonseed oil, ground-nut oil,corn germ oil, olive oil, viscoleo, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated iso-stearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite agar-agar and tragacanth,or mixtures of these substances, and the like.

Compositions for rectal administrations are preferably suppositorieswhich can be prepared by mixing the compounds of the present inventionwith suitable nonirritating excipients or carriers such as cocoa butter,polyethylene glycol or a suppository wax, which are solid at ordinarytemperatures but liquid at body temperature and therefore, melt in therectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

The term “pharmaceutically acceptable salts” as used herein refers tothose amino acid addition salts of the compound of the present inventionwhich are, the scope of sound medical judgment, suitable for use incontact with the tissues of patients without undue toxicity, irritation,allergic response, and the like, commensurate with a reasonablebenefit/risk ratio, and effective for their intended use as well as thezwitterionic forms, where possible, of the compounds of the invention.The term “salts” refers to the relatively non-toxic, inorganic andorganic acid addition salts of the compounds of Formula I. These saltscan be prepared in situ during the final isolation and purification ofthe compounds of the invention or by separately reacting the purifiedcompound in the free base form with a suitable organic or inorganic acidand isolating the salt thus formed. Representative salts include thehydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate,ox-alate, valerate, oleate, palmitate, sstarate, laurate, borate,benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionateand laurylsulphonate salts, and the like. These may include cationsbased on the alkali and alkaline earth metals, such as sodium,potassium, calcium, magnesium, and the like, as well as nontoxicammonium, quaternary ammonium and amine cations including, but notlimited to ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. (See, for example, S. M. Berge, et al., “PharmaceuticalSalts,” J. Pharm. Sci., 1977; 66:1-19 which is incorporated herein byreference.) In addition, the compounds of the present invention canexist in unsolvated as well as solvated form with pharmaceuticallyaccepted solvents such as water, ethanol, and the like. In general, thesolvated forms are considered equivalent to the unsolvated forms for thepurposes of the present invention.

According to a further aspect of the present invention there is provideda method of treating Parkinson's disease in a patient in need thereof,which method comprises administering to the patient a therapeuticallyeffective amount of a compound of any of formulae Ie, If and Ig, definedas above, or a pharmaceutically acceptable salt thereof.

A “therapeutically effective amount” is an amount of a compound ofFormula I, that when administered to a patient, ameliorates a symptom ofParkinson's disease.

Those skilled in the art are easily able to identify patients havingParkinson's disease. For example, patients who exhibit symptoms whichinclude, but are not limited to, tremor and/or shaking and difficultywith walking, other movement, and coordination.

According to another aspect of the present invention there is provided amethod of treating schizophrenia in a patient in need thereof, whichmethod comprises administering to the patient a therapeuticallyeffective amount of a compound of any of formulae Ib and Id, defined asabove, or a pharmaceutically acceptable salt thereof.

The compounds of the present invention can be administered to a patientat dosage levels in the range of about 0.01 to about 1,000 mg per day.For a human adult having a body weight of about 70 kilograms, a dosagein the range of about 0.001 to about 100 mg per kilogram of body weightper day is preferable. The specific dosage used, however, can vary. Forexample, the dosage can depend on a number of factors including therequirements of the patient, the severity of the condition beingtreated, and the pharmacological activity of the compound being used.The determination of optimum dosages for a particular patient iswell-known to those skilled in the art.

In addition, it is intended that the present invention cover compoundsmade either using standard organic synthetic techniques, includingcombinatorial chemistry or by biological methods, such as throughmetabolism. The examples presented below are intended to illustrateparticular embodiments of the invention and are not intended to limitthe scope of the specification, including the claims, in any way.

The compounds of Formula I, utilized in the method of the presentinvention, are ideally suited for several reasons. Firstly, thecompounds are stable, making them excellent candidates for oraladministration. Secondly, the compounds are long acting, therebyenabling effective treatment with fewer dosing intervals, which is ofsignificant importance for elderly patients. Thirdly, the compounds ofthe present invention have excellent oral bioavailabilities.

According to a further aspect the present invention provides thecompounds of formula (I) as defined above, however with no disclaimer inthe meaning of NR₁R₂ when rings B, C, D and E are absent, and thepharmaceutically acceptable salts thereof, for therapeutical use.

According to yet another aspect the present invention comprises the useof the compounds of formula (I) as defined above, however with nodisclaimer in the meaning of NR₁R₂ when rings B, C, D and E are absent,and the pharmaceutically acceptable salts thereof for the manufacturingof pharmaceutical compositions for the treatment of Parkinson's disease,psychoses, Huntington's disease, impotence, renal failure, heart failureor hypertension.

The following detailed examples illustrate the general synthetictechniques utilized for preparing the compounds, along with some of thebiological assays employed to establish the efficacy of the compounds ofthe present invention.

EXAMPLES (Alkylated) Dopamine Prodrugs

The lower scheme represents a Birch reduction.

Example 1 3-(2-Dipropylamino-ethyl)-cyclohex-2-enone (GMC6598)

3-Vinyl-cyclohex-2-enone (0.75 g, 6.1 mmol) (prepared according toNasarow's method) was dissolved in acetonitril (1 mL) and dipropylamine(1.5 g, 16 mmol) was added followed by Cs₂CO₃ (50 mg). After stirringthe mixture at rt for 3 h it was diluted with diethylether (100 mL),filtered and evaporated to dryness. The residue was destined in vacuo(175° C., 0.01 mm Hg) to give a slightly yellow oil which was convertedto the hydrochloride salt. Recrystallization from isopropylether/isopropyl alcohol yielded: 1.2 g, 4.6 mmol (75%), mp 95-97° C. IR(KBr) 2962, 2613, 1667; ¹H-NMR (CDCl₃) δ 5.84 (d, 1H), 2.65 (m, 2H),2.27-2.60 (m, 9H), 1.99 (m, 2H), 1.39-1.51 (m, 5H), 0.86 (t, 6H) ppm;¹³C-NMR (CDCl₃) δ 198.2, 163.5, 124.9, 54.2, 50.1, 35.7, 33.7, 28.4,21.2, 18.5, 10.4 ppm; MS (EI) m/z 223 (M⁺).

Example 2 3-(2-Diethylamino-ethyl)-cyclohex-2-enone (GMC6608)

The same procedure was used as in Example 1 but using diethylamine.Destillation at 120° C., 0.01 mmHg afforded a colorless oil that wasconverted to the hydrochloride salt. Recrystallization from isopropylether/isopropyl alcohol yielded: 1.3 g, 5.6 mmol (91%), mp 148-149° C.IR (KBr) 2948, 2851, 1661; ¹H-NMR (CDCl₃) δ 5.86 (d, 1H), 2.48-2.67 (m,6H), 2.27-2.39 (m, 6H), 1.96 (m, 2H), 1.02 (t, 6H) ppm; ¹³C-NMR (CDCl₃)δ 198.3, 163.5, 124.8, 48.9, 45.2, 35.7, 33.7, 28.4, 21.2, 10.1 ppm; MS(EI) m/z 195 (M⁺).

Example 3 3-(2-Dibutylamino-ethyl)-cyclohex-2-enone (GMC6623)

The same procedure was used as in Example 1 but using dibutylamine.Purification by column chromatography (silica, ethyl acetate) yielded acolorless oil that was converted to the hydrochloride salt.Recrystallisation from isopropyl ether/isopropyl alcohol gave 1.3 g, 5.6mmol (91%), nip 115-117° C. IR (KBr) 2959, 2494, 1661; ¹H-NMR (CDCl₃) δ5.84 (d, 1H), 2.60 (q, 2H), 2.26-2.44 (m, 8H), 1.96 (m, 3H), 1.21-1.46(m, 8H), 0.87 (t, 6H) ppm; ¹³C-NMR (CDCl₃) δ 198.2, 163.6, 124.9, 52.0,50.2, 35.7, 33.8, 28.4, 27.5, 21.2, 19.1, 12.5 ppm; MS (CI) m/z 252(M+1).

Example 4 3-(2-((2-Phenyl)ethyl-propylamino)-ethyl)-cyclohex-2-enone(GMC6624)

The same procedure was used as in Example 1 but usingN-propyl-2-phenylethylamine. Purification by column chromatography(silica, ethyl acetate) yielded a colorless oil that was converted tothe hydrochloride salt. Recrystallisation from ether/ethanol gave 1.8 g,5.6 mmol (91%), mp 110-112° C. IR (KBr) 2937, 2538, 2442, 1667; ¹H-NMR(CDCl₃) δ 7.15-7.83 (m, 5H), 5.95 (s, 1H), 3.07 (t, 2H), 2.83, (q, 2H),2.27-2.50 (m, 6H), 2.04 (p, 4H), 1.47-1.64 (m, 4H), 0.86 (t, 3H) ppm;¹³C-NMR (CDCl₃) δ 198.2, 163.5, 136.4, 127.2, 127.0, 126.7, 119.2, 48.1,42.7, 42.4, 36.2, 34.0, 32.2, 22.8, 20.7, 20.3, 9.4 ppm; MS (CI) m/z 286(M+1).

N-n-Propyl-3-(3,4-di-hydroxyphenyl)piperidine PRODRUG Scheme 2) Prodrugof 3-APC (Alkylpyridinecatechol)

Reagents: (a) Chloropropyl-alkylamine; (b) NaBH3CN

As for the dopamine prodrug, the same possibility for a Birch reductionis present

Example 5

a) 3-Ethynyl-2-cyclohexen-1-one (GMC6573)

To a solution of 0.5N ethynylmagnesium bromide in tetrahydrofuran (100mL) was added under N₂ and stirring 3-ethoxy-2-cyclohexen-1-one (3.75 g,26.8 mmol) in tetrahydrofuran (12.5 mL). The mixture was stirred at RTfor 20 h when it was acidified with 1N HCl (200 mL). After stirring for15 min the acidic phase was extracted with dichloromethane (5×50 mL).The combined organic extracts were washed with water (2×50 mL) and dried(MgSO₄). Evaporation of the solvent gave an oil that was purified bycolumn chromatography (silica, ethyl acetate/hexane 1:9) to yield ayellow oil, 2.71 g, 22.6 mmol, 84%). Analysis were in agreement withliterature data.

b) 3-(1-Propyl-1,4,5,6-tetrahydro-pyridin-3-yl)-cyclohex-2-enone(GMC6602)

3-Ethynyl-cyclohex-2-enone (3.20 g, 26.8 mmol) (from a) above) and(3-Chloro-propyl)-propyl-amine (4.50 g, 33.2 mmol) were mixed inacetonitril (50 mL). Cs₂CO₃ (100 mg) and KI (200 mg) were added and themixture was refluxed under N₂ for 10 h. After cooling the mixture wasdiluted with water (50 mL) and extracted with dichloromethane (3×50 mL).The combined organic layers were washed with brine, dried (MgSO₄) andevaporated. The resulting dark oil was purified by column chromatography(silica, ethyl acetate) to give a yellow red oil. Yield 5.1 g, 23.3 mmol(87%). IR (neat) 2932, 2871, 1589, 1538, 1157 cm⁻¹; ¹H-NMR (CDCl₃) δ6.84 (s, 1H), 5.69 (s, 1H), 3.04-3.12 (m, 4H), 2.44 (t, 2H), 2.33 (t,2H), 2.18 (t, 2H), 1.83-2.03 (m, 4H), 1.49-1.64 (m, 2H), 0.87 (t, 3H)ppm; ¹³C-NMR (CDCl₃) δ 197.0, 158.5, 140.1, 112.1, 102.4, 56.6, 44.3,35.6, 23.6, 21.4, 20.2, 20.1, 19.7, 9.6 ppm; MS (CI) m/z 220 (M+1).

c) 3-(1-Propyl-piperidin-3-yl)-cyclohex-2-enone (GMC6606)

3-(1-Propyl-1,4,5,6-tetrahydro-pyridin-3-yl)-cyclohex-2-enone (5.0 g,22.8 mmol) (from b) above) was dissolved in THF (100 mL). At 0° C.,acetic acid (1.38 mL, 22.8 mmol) was added followed by introduction ofNaBH₃CN (1.9 g, 30.0 mmol) in small portions maintaining thetemperature. After the addition was complete the mixture was stirred for1 h at this temperature and then at rt overnight. Work-up by addition ofwater (50 mL) and saturated aqueous NaHCO₃ (50 mL) followed byextraction with dichloromethane (5×50 mL). The combined organic layerswere dried (MgSO₄) and evaporated. The residue was purified by columnchromatography (silica, dichloromethane/ethanol 20:1) to give acolorless oil which was converted to the hydrochloride.Recrystallisation from isoprylether gave 4.2 g, 17.5 mmol (77%), mp184-185° C. IR (KBr) 3396, 2941, 2469, 1667, 1455 cm⁻¹; ¹H-NMR (CDCl₃) δ5.83 (s, 1H), 3.85 (d, 2H), 2.29-2.56 (m, 7H), 1.23-2.17 (m, 10H), 0.88(t, 3H) ppm; ¹³C-NMR (CDCl₃) δ 198.4, 165.1, 123.4, 59.0, 55.6, 51.9,41.6, 36.0, 27.3, 26.9, 22.8, 21.2, 17.6, 10.2 ppm; MS (EI) m/z 221(M+).

Reagents: (a) H₂, Pd/C; (b) SOCl₂, RNH2; (c) LiAlH₄; (d) Li, NH₃; (e)EtO₂C(CH₂)₃P(Ph)₃Br, K^(t)OBu; (f) PPA.

Or a different strategy:

Example 6

a) 3-(4-methoxyphenyl)-propionic acid n-propylamide (GMC6632)

3-(4-methoxyphenyl)-propionic acid (8.8 g, 49 mmol) was refluxed indichloromethane (200 mL) with thionyl-chloride (6.6 mL, 90 mmol) for 1h. The volatiles were evaporated and the resulting oil was dissolved indichloromethane (100 mL). This was added to a vigorously stirred mixtureof 5% aqueous NaOH (200 mL), dichloromethane (100 mL) and n-propylamine(3.0 mL, 71 mmol). After stirring for 1 h the layers were separated andthe aqueous layer was extracted with dichloromethane (3×50 mL). Thecombined organic layers were washed with water (50 mL) and brine (50 mL)and was dried over MgSO₄. Evaporation of the solvent gave the amide inquantitative yield (10.7 g, 49 mmol, 100%). IR (neat) cm⁻3300, 2961;1734, 1642; MS (EI) m/z 221 (M+) Analyses were in agreement withliterature data.

b) N-(3-(4-methoxyphenyl)-propyl)-N-propylamine (GMC6633)

To a stirred mixture of LiAlH₄ (8.0 g, 200 mmol) in tetrahydrofuran (100mL) was added dropwise a solution of 3-(4-methoxyphenyl)-propionic acidn-propyl amid (10.7 g, 49 mmol) (from a) above) in tetrahydrofuran (100mL). After refluxing for 12 h the mixture was cooled to 50° C. andexcess hydride was destroyed by careful addition of water (10 mL), 5%aqueous NaOH (40 mL) and water (20 mL) allowing reflux conditions. Thehot slurry was filtered and the white precipitate was washed thoroughlywith ethanol. Volatiles were evaporated and the resulting oil dissolvedin ethyl acetate (50 mL) what was extracted with 0.5 N aqueous HCl (4×50mL). The acidic phase was made alkaline (pH=9) by addition of 30%aqueous NaOH and extracted with ethyl acetate (4×50 mL). The organiclayers were combined, washed with brine, dried (MgSO₄) and evaporated todryness to give an oil that partially crystallized in diethyl ether asthe hydrochloride salt. Recrystallization from acetone/diethyl ethergave white flacky crystalline material. Total yield (as free base): 9.9g, 48 mmol, 98%, mp 176-177° C. IR (neat) cm⁻¹ 2960, 2772, 1611, 1514;¹H-NMR (CDCl₃) δ 9.46 (br s, 1H), 7.16 (d, 2H), 6.90 (d, 2H), 3.72 (s,3H), 2.82 (br s, 4H), 2.59 (t, 2H), 2.15 (p, 2H), 1.83 (h, 2H), 0.89 (t,3H) ppm; ¹³C-NMR (CDCl₃) δ 156.6, 130.3, 127.7, 112.4, 53.7, 47.9,45.66, 30.3, 25.9, 17.8, 9.7 ppm; MS (EI) m/z 207 (M+).

c) trans-N-propyl-7-keto-1,2,3,4,4a,5,8,8a-octahydro-[6H]-quinoline(GMC6638)

N-(3-(4-methoxyphenyl)-propyl)-N-propyl amine (6.15 g, 31.45 mmol) (fromb) above) was dissolved in THF (60 mL), t-BuOH (4.65 g, 5.93 mL, 62.89mmol). The mixture was cooled to −60° C. and liquid NH₃ (60 mL) wasintroduced. Then Li metal (1.70 g, 0.24 mol) was gradually added insmall portions and the blue mixture was stirred at −60° C. for 4 h. Thecolor was discharged by addition of a MeOH/aqueous NH₄Cl (sat) solution(1:1, 20 mL) and the cooling bath removed. After NH₃ had evaporated thepH of the slurry was adjusted to 1 by addition of concentratedhydrochloric acid and stirred for 24 h. Then the mixture was basified topH 10 (30% NaOH, T<15° C.) and solid NaCl was introduced until theorganic layer separated. The aqueous solution was extracted withdichloromethane (8×50 mL) and the combined organic layers ware washedwith brine and dried over MgSO₄. Evaporation yielded a red oil that waspurified by column chromatography (silica, dichloromethane/ethanol,20:1) to yield a colorless oil (4.69 g, 24.05 mmol, 76%). A sample wasconverted to the hydrochloride for analysis, mp 148-150° C. IR (KBr)2950, 2384, 1711, 1464 cm⁻¹; ¹H-NMR (CDCl₃) δ 3.10 (dt, 1H, J=3.91 Hz,9.52 Hz), 1.23-1.80 (m, 7H), 1.93-2.72 (m, 10H), 0.84 (t, 3H) ppm;¹³C-NMR (CDCl₃) δ 210.4, 59.5, 54.3, 46.3, 36.6, 36.0, 33.7, 26.8, 23.6,22.7, 18.0, 10.3 ppm; MS (EI) m/z 195 (M+).

d)L-Propyl-trans-2,3,4,4a,5,7,8,9,10,10a-decahydrobenzo[g]quinolin-6-one(GMC6650) and1-Propyl-cis-2,3,4,4a,5,7,8,9,10,10a-decahydrobenzo[g]quinolin-6-one(GMC6651)

To a cooled (0° C.) suspension of KO^(t)Bu (2.5 g, 25.6 mmol) in drydimethylformamide (4 mL) flushed with N₂ was added dropwise a solutionof (3-ethoxycarbonylpropyl) triphenylphosphonium bromide (12.9 g, 28.2mmol) in dry, N₂ flushed dimethylformamide (25 mL). When the additionwas complete the mixture was stirred at 0° C. for 30 min. Then asolution oftrans-N-propyl-7-keto-1,2,3,4,4a,5,8,8a-octahydro-[6H]-quinoline (2.5 g,12.8 mmol) (from c) above) in dry, N₂ flushed dimethylformamide (4 mL)was added dropwise at 0° C. After stirring at 0° C. for 4 h thetemperature was allowed to rise to RT and stirring was continuedovernight. Water (50 mL) was added and the mixture was filtered throughCelite (2 g). The filtrate was extracted with hexane (5×25 mL). Thecombined organic layers were dried (MgSO₄), filtered and evaporated togive a beige solid (9.1 g). The solid was dissolved in dichloromethane(10 mL) and was added to PPA (40 g) at 100° C. while stirring. After 4 hstirring at that temperature the reaction mixture was allowed to cool toabout 80° C. when crushed ice (50 g) was introduced. Stirring wascontinued at that temeprature for 1 h and then the solution was allowedto cool to RT. Concentrated ammonia was added until pH=8 and then thesolution was extracted with dichloromethane (6×100 mL). The combinedorganic layers were dried (MgSO₄), filtered and evaporated. The residuewas purified by column chromatography (silica, dichloromethane/methanol,gradient) and the products were subsequently converted to thehydrochloric salt and recrystallized from diethyl ether/ethanol.

Cis isomer: Yield 0.07 g, 0.3 mmol (6%). IR (KBr) 2928, 2592, 1668,1457, 1394 cm⁻¹; ¹H-NMR 500 MHz (CDCl₃) δ 3.20 (t, 1H, J=11 Hz), 2.75(d, 1H), 2.00-2.58 (m, 12H) 1.82-2.00 (m, 2H), 1.52-1.79 (m, 4H), 1.38(d, 1H), 1.22-1.29 (dq, 1H), 0.90 (t, 3H) ppm; ¹³C-NMR (CDCl₃) δ 197.3,151.1, 128.7, 54.8, 53.5, 45.1, 36.3, 31.0, 29.7, 26.3, 24.0, 23.3,22.6, 20.9, 18.0, 10.3 ppm; MS (EI) m/z 249 (M+) Trans isomer: Yield0.61 g, 2.2 mmol (67%), mp 235° C. IR (KBr) 2928, 2592, 1668, 1457, 1394cm⁻¹; ¹H-NMR 500 MHz (CDCl₃) δ 3.06 (d, 1H, J=11.2 Hz), 2.72-2.78 (dt,1H), 2.15-2.55 (m, 10H),1.51-1.99 (m, 9H), 1.01-1.10 (dq, 1H), 0.89 (t,3H) ppm; ¹³C-NMR 200 MHz (CDCl₃) δ 197.0, 152.6, 129.8, 59.6, 53.6,51.2, 36.1, 35.2, 34.9, 29.3, 29.4, 28.1, 23.2, 20.8, 15.8, 10.4 ppm; MS(EI) m/z 249 (M+).

Example 71-Propyl-trans-2,3,4,4a,5,7,8,9,10,10a-decahydrobenzo[g]quinolin-6-one(GMC6650) and1-Propyl-cis-2,3,4,4a,5,7,8,9,10,10a-decahydrobenzo[g]quinolin-6-one(GMC6651)

A solution of 3-ethynyl-2-cyclohexen-1-one (GMC6573) (Example 5a) (1.80g, 15.0 mmol) in 1,2-dichlorobenzene (50 mL) was added to a solution of1-propylamine-4-pentene in 1,2-dichlorobenzene (50 mL). The solution wasstirred for 30 min at rt then for 72 h at 190° C. After cooling themixture was poored in 4N HCl (40.0 mL) and this was stirred at rt for 2h. The acidic layer was separated and extracted with diethylether (2×50mL). Then the aqueous layer was made alkaline (pH=8) with concentratedammonia and was extracted with dichloromethane (5×50 mL). The combinedorganic layers were washed with brine (50 mL) and dried (MgSO₄).Evaporation gave a dark oil that was purified by column chromatography(silica, dichloromethane/methanol, gradient) and subsequently convertedto the hydrochloride, which was isolated in 2% yield. Analysis data wereas in Example 6.

This procedure was repeated by rather than working in1,2-dichlorobenzene solution the reactants were reacted neat at 300° C.When working in this way the yield was considerably improved.

Example 8 Resolution of1-Propyl-trans-2,3,4,4a,5,7,8,9,10,10a-decahydrobenzo[g]quinolin-6-one(GMC6650)

A 5 mg mL⁻¹ solution of racemic GMC6650 prepared as illustrated inExample 6, in hexane/isopropanol (4/1 (v/v)) was injected into a HPLCsystem using a Water 510 HPLC pump fitted with a 500 μL loop and aChiralpack AD semi-preparative column (250×10 mm). Mobile phase was amixture produced by an ISCO Model 2360 Gradient Programmer and consistedof 98% hexane (containing 0.1% (w/w) triethylamine) and 2%isopropanol/hexane (1/1 (w/w)). Flow of the mobile phase was 4.0 mLmin⁻¹. The separate enantiomers were detected by a Water 486 MilliporeTunable Absorbance Detector (λ=254 nm, AUFS=2.0) and were recorded onpaper using a Kipp & Zonen flatbed recorder (chart speed 5 mm min⁻¹,α=1.33; k₁′=2.16; k₂′=2.88). Fractions were collected by hand. Afterevaporation of the mobile phase the optical rotation of the twofractions was determined using a Perkin Elmer 241 Polarimeter. Firsteluting fraction: [α]_(d) ²⁰=+185° (c=0.08, methanol). Second elutingfraction: [α]_(d) ²⁰=−214° (c=0.07, methanol). Both enantiomers wereanalyzed for their purity using the same HPLC system but now fitted witha Chiral-pack AD analytical column (250×4.6 mm) and a 20 μL loop(e.e.=>99.9% for both enantiomers). Both enantiomers were converted totheir corresponding maleate salts and were recrystallized fromethanol/diethylether. Melting points: (+)-GMC6650.Maleate mp: 186° C.,(−)-GMC6650.Maleate mp: 192° C.

Reagents: (a) Chloropropyl-alkylamine; (b) NaBH₃CN

Example 9 N-Propyl-benzo[f]quinoline ProdrugN-propyl-8,9-dihydro-10H-aporphin-11-one

a) Method 1:

To a stirred solution of 3,4,7,8-tetrahydro-2H,5H-naphthalene-1,6-dione(0.5 g, 3.0 mmol) in dry acetonitril (15 mL) is added3-chloropropyl-propylamine (0.38 g, 3,0 mmol). The mixture is heated to80° C. under argon for 36 h. The reaction mixture is then cooled to RTand diluted with ether (25 mL). Filtration and evaporation of thesolvents yields an oil that is dissolved in tetrahydrofuran (15 mL) andcooled to 0° C. The crude product is reduced with NaBH₃CN under acidicconditions. Work-up is performed in the usual way and the products arepurified by column chromatography and the separated cis and transproducts are subsequently converted to a pharmaceutically acceptablesalt and recrystallized, yielding the desired products.

b) Method 2:

1,3-cyclohexadione (0.2 mol), paraformaldehyde (0.2 mol),(3-chloropropyl)-propylamine (0.2 mol) and powdered 4 Å molesieves aremixed in toluene. The mixture is heated and acetone (0.2 mol) isintroduced and heating is continued. The reaction mixture isconcentrated in vacuo then washed through a column of silica. Thefractions containing the product are combined and concentrated. Thismaterial is further purified by column chromatography. The purifieddienaminone is reduced with NaBH₃CN under acidic conditions. Work-up inthe usual way and the products are purified by column chromatography andthe separated cis and trans products are subsequently converted to apharmaceutically acceptable salt and recrystallized, yielding thedesired products.

Keto-transposition and attachment of the 4^(th) ring:

Reagents: (a) NaBH₄; (b) 6N HCl; (c) i) BrCH₂CONH₂, HCO₂H; ii) NaOH; (d)Wittig reaction; (e) PPA.

Benzyne strategy:

N-Propyl Aporphine Prodrug

Example 10

a) 3-aminophenylacetic acid ethyl ester (GMC6635)

To a cooled solution (−15° C.) of 3-aminophenylacetic acid (10.2, 67mmol) in ethanol (200 mL) was added dropwise thionyl chloride (10 mL,0.14 mol). The reaction mixture was stirred for 24 h allowing thetemperature to slowly rise to rt. Evaporation of the volatiles gave abeige solid that was stripped several times with dichloromethane. Thesolid was then treated with hot diethyl ether and filtered to removediethyl sulphite. Recrystallization from dietyl ether gave 14.4 g, 67mmol, 100% of the desired compound as an off-white crystallinehydrochloride, mp 135° C. IR (KBr) cm⁻¹ 2857,2614, 1740

b) N-propyl-2-(3-aminophenyl)ethylamine (GMC6636)

3-Aminophenylacetic acid ethyl ester hydrochloride (2.7 g, 13 mmol) wasadded to n-propylamine (20 mL) while stirring and cooling to 0° C. Afterstirring for 45 min the reaction mixture was evaporated to give acolorless solid of the amide product. The amide was dissolved intetrahydrofuran (20 mL) and 2N BH₃.SMe₂ in tetrahydrofuran (20 mL) wasadded at −10° C. After stirring at that temperature for 2 h the mixturewas refluxed for 48 h. The mixture was extracted to give the amine whichwas converted to the hydrochloride salt. Recrystallisation fromacetone/diethyl ether gave 2.2 g, 10 mmol (77%), mp 175° C. IR (KBr)2928, 2592, 1457, 1394 cm⁻¹; MS (EI) m/z 178 (M⁺).

c) N-propyl-8,9-dihydro-10H-11-oxo-aporphine (GMC6660)

A solution of 3-ethynyl-2-cyclohexen-1-one (GMC6573) (1.80 g, 15.0 mmol)in toluene (5 mL) was added to a solution ofN-propyl-(3-aminophenylethyl)amine (2.67 g, 15.0 mmol, free base)toluene (5 mL). The solution was stirred for 30 min and subsequentlyextracted with 6N HCl solution (2×4 mL). The acidic solution was cooledto 0° C. and a solution of NaNO₂ (0.69 g, 100 mmol) in water (15 mL) wasadded slowly maintaining 0° C. After the addition was complete themixture was allowed to warm up to RT and was stirred untill all startingmaterial and diazonium intermediate were consumed. The acidic solutionwas extracted with ethyl acetate (2×20 mL), made alkaline (pH≈8), andwas extracted with dichloromethane (4×20 mL). The combined organiclayers were washed with saturated NaCO₃ solution (50 mL) and dried(MgSO₄). Evaporation gave an oil that was purified by columnchromatography (silica, dichloromethane/ethanol, 40:1) and the pureproduct was subsequently converted to the hydrochloric salt to 3.18 g,10 mmol (67%), mp 210-212° C. IR (KBr) 2948, 2851, 1661; ¹H-NMR (CDCl₃)δ 5.86 (d, 1H), 2.48-2.67 (m, 6H), 2.27-2.39 (m, 6H), 1.96 (m, 2H), 1.02(t, 6H) ppm; ¹³C-NMR (CDCl₃) δ 198.3, 163.5, 124.8, 48.9, 45.2, 35.7,33.7, 28.4, 21.2, 10.1 ppm; MS (CI) m/z 282 (M+1).

Example 11

N-n-propyl-1,3,4,4a,5,6,8,9,10,10b-dekahydro-2H-benzo [f]quinolin-7-one

1-Propyl-7-oxo-2,3,7,8,9,9a-hexahydro-1H-benzo[de]quinoline is reducedto the corresponding alcohol and subsequently dehydrated. The exocyclicdouble bond is epoxidized followed by a ring opening thus forming1-propyl-6-oxo-2,3,6,8,9,9a-hexahydro-1H-benzo[de]quinoline. This ketoneis subjected to a Wittig reaction with(3-ethoxycarbonylpropyl)-triphenylphosphonium bromide. After the usualwork-up the crude product is dissolved in dichloromethane and is addedto PPA. After the cyclization is complete the product is allowed tohydrolyze under acidic conditions. Extraction after basification givesthe crude end product. This is purified by column chromatography and theproducts were subsequently converted to a pharmaceutically acceptablesalt and recrystallized.

Pharmacology Behavioral Testing in Rats of Compound GMC6650 (Example 6)

One rat, weighing about 350 g, was injected SC in the neck with 1μmol/kg of GMC6650. Another rat, weighing about 350 g, was injected POwith the same dose. The drug (3.4 mg) was initially dissolved in:ethanol (50 μL), 1 M acetic acid (2 drops), and water (1.4 mL),corresponding to 15 μmol per 1.5 mL, which means a concentration of 10μmol/mL. By first diluting that solution 10 times and injecting 0.35 mL,the given dose will be 1 μmol/kgμmol/kg. This goes for both of rats.

Independent of which kind of administration the rats had received, bothindividuals displayed the same pattern of biological activity: after 10minutes the rats became sedated, closing or partly closing their eyes.After 15 minutes obvious dopaminergic effects were seen, i.e. chewing,sniffing, licking, penile grooming, grooming, and after 30 minutes bothrats showed clear signs of stereotypy.

Stereotypy was intense and was registered for several hours by visualinspection. After 10 hours both rats were still showing signs ofstereotypy. The next morning, the SC rat was still active, while the POrat was resting. Duration of action was thus ≧10 h for both sc and poadministration of 1 μmol/kg.

The invention claimed is:
 1. Compounds of the following general formulaIf:

wherein m is an integer 1-3 and R₂ is selected from the group consistingof a hydrogen atom, alkyl or haloalkyl groups of 1 to 7 carbon atoms,cycloalkyl (alkyl) groups of 3 to 7 carbon atoms, alkenyl or alkylnylgroups of 3 to 6 carbon atoms, arylalkyl, heteroarylalkyl having 1 to 3carbon atoms in the alkyl moiety, in which the aryl/heteroaryl may besubstituted; and salts thereof with pharmaceutically acceptable acids orbases.
 2. Compounds according to claim 1, wherein R₂ is n-propyl.
 3. Amethod of treating Parkinson's disease in a patient in need thereof,which method comprises administering to the patient a therapeuticallyeffective amount of a compound of formula If as defined in claim 1 or apharmaceutically acceptable salt thereof.
 4. A compound selected fromthe group consisting of:

wherein m is an integer 1-3, n is an integer 1-3, R₁ is selected fromthe group consisting of an alkyl or haloalkyl groups of 1 to 3 carbonatoms, R₂ is selected from the group consisting of an alkyl or haloalkylgroups of 1 to 7 carbon atoms; and substantially pure chiral forms andpharmaceutically acceptable salts thereof.
 5. The compound of claim 4,wherein said compound is


6. The compound of claim 4, wherein said compound is Formula Ib havingthe following substantially pure enantiomeric form:


7. The compound of claim 4, wherein said compound is


8. A compound having a substantially pure enantiomeric form selectedfrom the group consisting of:

wherein m is an integer 1-3, n is an integer 1-3, R₂ is selected fromthe group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1to 7 carbon atoms; and pharmaceutically acceptable salts thereof.
 9. Thecompound of claim 7, wherein R₁ is n-propyl.
 10. The compound of claim6, wherein R₂ is n-propyl.
 11. A compound according to claim 4, which is3-(1-propyl-piperidin-3-yl)-cyclohex-2-enone; or the pharmaceuticallyacceptable salt thereof.
 12. A pharmaceutical composition which containsa compound, said compound selected from the group consisting of:

wherein m is an integer 1-3, n is an integer 1-3, R₁ is selected fromthe group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1to 3 carbon atoms, R₂ is selected from the group consisting of ahydrogen atom, alkyl or haloalkyl groups of 1 to 7 carbon atoms; andsubstantially pure chiral forms and pharmaceutically acceptable saltsthereof, together with a pharmaceutically acceptable carrier, diluent orexcipient.
 13. A pharmaceutical composition which contains a compound,said compound selected from the group consisting of:

wherein m is an integer 1-3, n is an integer 1-3, R₂ is selected fromthe group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1to 7 carbon atoms; and substantially pure chiral forms andpharmaceutically acceptable salts thereof, together with apharmaceutically acceptable carrier, diluent or excipient.
 14. A methodof treating Parkinson's disease in a patient in need thereof, whichmethod comprises administering to the patient a therapeuticallyeffective amount of a compound or a pharmaceutically acceptable saltthereof, wherein said compound or pharmaceutically acceptable saltthereof is selected from the group consisting of:

wherein m is an integer 1-3, n is an integer 1-3, R₁ is selected fromthe group consisting of a hydrogen atom, alkyl or haloalkyl groups of 1to 3 carbon atoms, R₂ is selected from the group consisting of ahydrogen atom, alkyl or haloalkyl groups of 1 to 7 carbon atoms; andpharmaceutically acceptable salts thereof.
 15. The method of claim 14,wherein said compound is

or pharmaceutically acceptable salts thereof.
 16. The method of claim14, wherein said compound is

or pharmaceutically acceptable salts thereof.
 17. The method of claim15, wherein R₂ is n-propyl.
 18. The method of claim 16, wherein R₁ isn-propyl.